Relapsed/refractory clinically advanced (CA) testicular non-seminomatous germ cell tumors (NSGCT): A genomic landscape study.

618 Background: The successful outcome for most men with NSGCT of testis after surgery and, in some cases, chemotherapy is a milestone in oncology. However, a minority of patients may become platinum-refractory with relapse or progression after chemotherapy. Comprehensive genomic profiling (CGP) has the potential to uncover new therapy targets for these patients. Methods: Hybrid capture based CGP was performed using the FoundationOne CDx assay on 182 CANSGCT to identify all classes of genomic alterations (GA). The site of the analyzed sample was available in 161/182 patients: 12.4% locoregional lymph nodes, 16.8% testis, 70.8% distant metastases. Microsatellite instability status (MSI), tumor mutational burden (TMB) and Homologous Recombination Deficiency (HRDsig) were determined from the sequencing data. Genomic ancestry and Cosmic trinucleotide signatures were also identified. PD-L1 expression was determined by IHC using Dako TPS score (0% = negative; 1-49% = low positive and ≥50% = high positive). Most cases had relapsed after surgery and chemotherapy, either loco-regionally or with metastatic disease at the time of CGP. Results: 182 men with CANSGCT had median age of 33. Genomic ancestry revealed that 65.4% of patients were European, 29.1% were admixed American, 3.3% were African, 1.6% were East Asian and 0.5% were South Asian. There was a median of 3 GA per sequenced tumor. At 2.2% frequency, MSI-high status was rare and TMB was relatively low with 95% of cases having TMB < 10 mut/Mb. A positive HRD signature was identified in 4.7% of cases. Identification of specific genomic signatures was uncommon with 2.7% having MMR signature and 1.1% having a tobacco exposure signature. PD-L1 expression was low level in 18.1% and high level in 15.3% of cases. KRAS mutations were the most frequent individual GA with <1% KRAS G12C. Inactivation of PTEN (6.6%) and activation of KIT (4.9%) were GA with potentially associated targeted therapies. Conclusions: CGP of CANSGCT cases revealed potential therapy targets with opportunities for clinical trials, e.g. focused on PTEN/MTOR pathway and KIT. Although initial clinical experience with targeted agents and anti-PD1/L1 have yielded limited benefit in unselected patients with these tumors, further CGP-based study of refractory NSGCT is warranted to enable the development of biomarker-driven clinical trials designed to rescue men who exhibit platinum refractory disease. Study limitations include the retrospective nature, lack of comparison with the genomic landscape of platinum-sensitive tumors, lack of clinical outcomes data annotation, selection and confounding biases.